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"Studying genetics is important, there is so much power in knowing what lies within the human genome. And only by understanding this can we begin to shed light on the mechanisms underlying ordinary human sensation." - E.C. Geneticist

The sensation of pain is a very complex phenotype, which arises from complex polygenic and environmental interactions. The modulation of pain, such as changing or inhibiting the transmission of pain impulses, has been implicated to have a heritable genetic component 1. The increase or decrease in the amount of pain sensitivity is linked to certain genes that code for a variety of different proteins in the body, such as different channels, enzymes, and cytokines. The variation found within these genes account for the differences in pain perception between individuals.

1.1. Heritability of Pain

Pain is a physiological response that warns the body of danger. Modulation of pain, which is the changing and inhibiting of the transmission of pain impulses, differs between individuals. The discrepancy is caused by the differences in certain genes coding for proteins that can increase of decrease the transmission of pain, as well as the complex interaction of environmental factors.1 Heritability estimates of 30-76%, based on inbred laboratory mice, suggest that the variance in pain response is due to genetic factors.2 African-Americans and non-Causasian Hispanics also report more pain compared to Caucasians, suggesting race and ethnicity play a role in discrepancies in pain thresholds.3 Females also typically report greater pain than males do, illustrating a role that gender plays in pain as well.4
Several genetic heritability studies show that the genes that alter pain modulation can be passed down from parents to offspring, and establish a heritable nature of both experimental and clinical pain. Twin studies show a 30-60% of variation in chronic pain syndromes may be accounted for by heritable factors.1 Another twin study showed 22-55% of genetic components were significant in responses for the majority of painful stimuli, such as hyperalgesia.5 Certain chronic pain disorders, such as fibromyalgia, show a concordance rate of about 50%.6 Genome wide association studies (GWAS) for chronic widespread pain (which stands at a 48-52% heritability rate) found a major hit at the chromosomal 5p15.2 region, which is associated with joint-specific chronic widespread pain in humans.7 These statistics provide evidence for the heritability of pain genes, which has major implications clinically in spearheading individualized treatment for patients. Therefore, studying these pain genes and their effects on the modulation of pain are important in combatting pain disorders, painful symptoms, and everyday painful stimuli.

1.2. Genes that Modulate Pain Sensitivity

Increasing pain sensitivity is one aspect of pain modulation that can be altered. There are several genes that, when altered, increase pain an individual feels. There are a variety of proteins that these genes code for, such as different ion channels (potassium8, sodium9, calcium10), adrenergic receptors11, and enzymes.12 Another way pain modulation can be altered is decreasing nociceptive transmission. Again, alteration of several genes can achieve this effect. Some of the genes that participate encode for proteins such as enzymes1314, opioid15 and melanocortin16 receptors, as well as cation channels.17Genetic variants may not only affect the protein the gene is coding for, but they may also have downstream effects, which could contribute to alterations in certain processes. Because of this, there are no definitive genes that simply modify pain sensitivity one way, as each gene is incorporated in a multitude of processes. There is no clear-cut group of genes that strictly increase pain sensitivity, or decrease pain sensitivity, although as mentioned before some genes are more inclined to do one or the other. The genes mentioned in the sections below are more of the well-researched pain genes, and how functional genetic variants account for differences in individual pain sensitivity.

1.2.1. SCN9A

Abnormalities in SCN9A

Different outcomes of mutations in the SCN9A gene.
Photo from:Institut für Humangenetik

SCN9A is a gene that encodes for a type IX alpha subunit of a voltage gated sodium channel, generally found in nociceptors.18 Peripheral neurons with this voltage-gated sodium channel are essential for pain and olfaction in both mice and humans.19
Mutations in this gene, which make abnormal Nav1.7 proteins, cause a variety of pain disorders. Inherited erythromelalgia (IEM) is a peripheral pain disorder, where blood vessels (usually in the extremities such as hands and feet) are episodically blocked. One of the causes is due to a change in one protein building block of the Nav1.7 channel, causing the channel to open more easily and remain open for longer. This increases the flow of sodium ions that produce nerve impulses, which enhances the transmission of pain signals.20Paroxysmal extreme pain disorder is a condition containing severe pain attacks on various parts of the body (notably mandibular, ocular, and rectal areas). A mutation change in a single amino acid of the alpha subunit of the Nav1.7 channel has been speculated to be a cause, as the channel would not be able to close completely. Inability to close this channel leads to abnormal sodium flow into the nociceptors, which enhances pain transmission.21 Another disorder with the same mechanism is small fibre neuropathy, which comprise of severe pain attacks on various regions of the body.22 Each of these disorders manifest when there is a mutation of the SCN9A gene, which highlights the importance of genetic studies in order to create better therapeutic agents to target this gene.

1.2.2. COMT

COMT in Action

Activity of COMT in the neuron, breaking down monoamines.
Photo from:www.CNSforum.com

COMT is a gene that codes for catechol-o-methyltransferase (COM), which is an enzyme that breaks down catecholamines such as dopamine, norepinephrine, and serotonin. One of the most abundant functional polymorphisms of COMT is the substitution of amino acid valine (val) with methionine (met) at codon 158.23 Being homozygous for met decreases COM enzymatic activity three-fold, being heterozygous with met/val provides intermediate enzymatic activity, and being homozygous for val is when COM is most effective.24
In animal models, met/met homozygotes display a reduced activity of COM, which allows for the increase in dopamine. The continuous activation of D2 dopaminergic receptors decreases the amount of enkephalin peptides found in the brain. The decrease is then followed by an up-regulation of μ-opioid receptors, as a compensatory course of action. The val/val homozygotes displayed opposite effects, due to a drastic increase in COM activity. This increase would maintain appropriate levels of dopamine, increased levels of enkephalins, and increased efficacy of the μ-opioid receptor to ligand activation. 25 The variability in the gene coding for COM is said to explain about 10% of variability seen in pain sensitivity.25 This polymorphism has been associated with increased pain, as met/met homozygotes have decreased capacity to activate μ-opioid neurotransmission.23 The differences in COM activity, as well as μ-opioid system activation induced by genetic variations in the COMT gene are important in understanding effects of opioid derived drugs on patients.26 By looking at the genetic make-up of a patient, different doses of opioid derived painkillers could be given, again leading to a more personalized medical treatment.

1.2.3. TRPV1

TRPV1 is a gene that codes for a transient receptor potential cation channel, subfamily V, member 1 that is expressed in a subpopulation of myelinated Aδ and unmyelinated C-fibres. It belongs to a family of nonselective cation channels that partake in a variety of processes, including temperature sensation in humans. It was previously known as a capsaicin receptor, and TRPV1 expressing primary sensory neurons release an assortment of pro-inflammatory neuropeptides that cause neurogenic inflammation.27 TRPV1 is sensitive to a variety of stimuli, such as noxious heat (above 43°C), acidosis, and capsaicin.28Pro-inflammatory agents can directly or indirectly enhance the probability of this channel opening through allosteric modification, resulting in TRPV1 acting as a molecular amplifier for the sensory neuron with the help of protein kinase A (PKA).29 Knock-out mouse models, as well as blocking of this gene show to decrease heat hyperalgesia.30
The balance between phosphorylation and dephosphorylation of the TRPV1 receptor controls the activation/ desensitization state of that channel. Certain models have taken advantage of this property, and TRPV1 has been the target of novel therapeutic interventions. An example of this is "capsaicin desensitization", where capsaicin (or any TRPV1 agonist such as RTX) can desensitize sensory fibres for patients experiencing disabling pain conditions through repeated applications, as well as block the activity of other receptors co-expressed with TRPV1.31 Agonists, however, are initially painful and can only be applied topically. More commonly used are TRPV1 antagonists, because of mouse-work and pharmacological blockage of the receptor itself. Antagonists block some TRPV1 activation, but can be safely administered.27 Therefore, by understanding the mechanisms behind how certain receptors work, patients will be able to receive care tailored to their individual needs.

I think its pretty interesting content wise, though I must say that the aesthetic appeal is rather disconnected (the light brown hue makes it unnecessarily difficult to read certain texts at times). Personally, I think the movement of pictures to the right side (leaving the text to format freely to the left), and use of coloured text modestly would help improve the visual appeal. Just reading through it, I don't really catch what the blue text is trying to emphasize. Just my two cents.

Great job, very well researched content. The color coding is useful to highlight the important aspects, however the light brown / beige color is somewhat difficult to read against the white background.

This is my favorite Neurowiki, because this topic is very extremely interesting. I never knew that pain was heritable and could be linked to gene expression and other genetic pathways!! It was very comprehensive and well organized. The Images and video were very informative, overall making it amazing!